Autoimmune diseases are diseases caused by an abnormal immune system in which the immune system does not work normally to produce humoral or cellular immune response to self-cells or self-tissues and an autoantibody responding to self-cells and self-tissues appear.
It is known that an autoantibody attacks self-cells or self-tissues to injure their function and as a result causes autoimmune diseases. Moreover, it has recently been reported that the autoantibody is detected in the patient's serum prior to occurrence of an autoimmune disease.
This means that detection of an autoantibody permits an early discovery or precognition of occurrence of an autoimmune disease, or precognition of deterioration of the disease condition, which allows early treatment or preventive therapy of the autoimmune disease.
Based on these findings, a variety of autoantibodies against autoantigens have been discovered and the autoantibodies against autoantigens have been measured in clinical tests.
For example, in a case of autoimmune diabetes mellitus, as relevant autoantibodies, an islet cell antibody (hereinafter abbreviated to ICA), islet cell surface antibody (hereinafter abbreviated to ICSA), anti-insulin antibody, anti-glutamic acid decarboxylase antibody, anti-ganglioside antibody, anti-bovine lactoalbumin antibody, anti-pancreatic cytokeratin antibody, and the like have been reported. In the above-mentioned autoimmune diabetes mellitus, ICA and ICSA can be detected in serum of the patients at a high frequency at the time of development of insulin-dependent diabetes mellitus (hereinafter abbreviated to IDDM). Particularly, ICA can be detected in serum of the patients prior to development of IDDM, which is accordingly known as a marker for preconceiving development of IDDM.
As mentioned above, many of IDDM patients are considered due to autoimmune diabetes mellitus developed in the autoimmune system, though it is reported that in some patients no autoantibody can be detected.
To the contrary, as for non-insulin-dependent diabetes mellitus (hereinafter abbrebiated to NIDDM), for example, the existence rate of ICA in IDDM patients is 40% or more, while that in NIDDM patients is deemed less than about 3% (Kobayashi T et al., Diabetes, Vol. 35, 335-340 (1986)). Thus, though the positive rate of autoantibody is high in IDDM, it is low in NIDDM, and there is no report on an effective autoantibody as a diagnostic marker for NIDDM.
On the other hand, a Reg (regeneration gene) protein was a protein discovered from the gene in which the expression is recognized markedly during regeneration of the Langerhans islets by administering nicotinamide to about 90% excised pancreas in rats (Terazono et al., Journal of Biological Chemistry, 263: 2111-2114 (1988)).
Reg proteins are found in human, rat, mouse, cattle, and hamster and now classified into three sub-types, i.e., Reg I, Reg II and Reg III, from the homology of their primary structures and the presence of the insertion sequence of 7 or 5 amino acid residues.
Reg proteins can be found not only in the above-mentioned Langerhans islet cells but also in liver, intestine, cancer cells in pancreas, and the mucous membrane of the small intestine, and reportedly appear during regeneration of nerve or gastric wall or at the time of development of pancreatitis. Accordingly, Reg proteins are considered widely involved in regeneration and proliferation of intracorporeal organs.
However, so far there is no report on the existence of autoantibodies against Reg proteins and autoimmune diseases caused thereby.